The invention relates to the combinatorial approaches to the preparation of novel polymer-supported heteroatom bidentate (PN, PO, PS) ligand libraries and the corresponding free compounds after cleavage from the supports. These compounds are useful as novel ligands in the preparation of metal-containing catalysts.
Chelating phosphine compounds bound to metal atoms are useful as catalysts. To facilitate separation of the catalysts from a chemical process, phosphorus ligands have been attached to solid supports such as polymers. Interest in using the combinatorial xe2x80x9csplit-and-mix synthesisxe2x80x9d approach to generate polymer-bound ligands which could be tested as catalysts has brought to fore the importance of new chemistry with which to attach phosphine ligands to polymer supports.
Novel processes have been discovered to prepare new compositions of matter that contain chelating phosphine compounds, including compounds of asymmetric and unsymmetric diphosphines using solid supports. Phosphine compounds have been shown to be useful when combined with transition metals as catalysts for chemical processes. The processes can also be utilized in a combinatorial scheme to produce libraries of phosphine compounds. These processes and the compounds prepared are described in U.S. patent application Ser. No. 09/415,347, filed Oct. 8, 1999.
Rapid, clean, high-yielding processes are needed, however, in which a variety of phosphine ligands are prepared. Especially needed are processes to prepare heteroatom bidentate phosphine ligands which are difficult to prepare using traditional methods as the intermediates are generally unstable. Processes are also needed that prepare these ligands in a library format and use chiral substituents.
The invention is directed towards a process to prepare a supported phosphine compound of Formula 1: 
wherein SS is a solid support; R1 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R2 is selected from the group consisting of halogen, cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic. The process comprises the steps of: a) contacting a phosphine of the formula XPR1R2, wherein X is a halogen, with the solid support, resulting in the P in the phosphine attached indirectly or directly to the solid support via covalent bonds, and b) optionally replacing one or more of R1 or R2 with any other R1 or R2 respectively.
Preferably, SS is selected from the group consisting of polyolefins, polyacrylates, polymethacrylates, and copolymers thereof.
Also preferably, the supported phosphine compound is of Formula 1A: 
wherein Z is a divalent or trivalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NQxe2x80x94, where Q is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen; and L is a divalent linking group covalently attached to Z and to SS, selected from the group consisting of optionally-substituted chains of from 1 to 12 linear, branched, and cyclic carbon atoms. Most preferably, SS is polystyrene; L is xe2x80x94CH2xe2x80x94; Z is xe2x80x94(NQ)xe2x80x94; Q is selected from the group consisting of n-propyl, and t-butyl; R1 is selected from the group consisting of bromo, chloro, phenyl, methyl, i-propyl, mesityl, cyclohexyl, 3-methoxyphenyl, and 2-thienyl, xe2x80x94CH2CH(C2H5)CH2O(CH2)3CH3, and xe2x80x94CH2CH(C2H5)CH2OCH2C6H5; and R2 is selected from the group consisting 2-furanyl, 2-(5-methylfuranyl), 2-thienyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-N,N-dimethyl-5-toluidinyl, 4-pyrrolidino-3-pyridinyl, 2,5-dimethyl-1-N(4xe2x80x2-methylphenyl)pyrrolidinyl, p-[(2,5-dimethyl)-1-pyrrolidinyl]phenyl, and 2,5-dimethoxylphenyl.
The invention is also directed towards supported phosphine compounds of Formula 1: 
wherein SS is a solid support; R1 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R2 is selected from the group consisting of cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic.
Preferably, SS is selected from the group consisting of polyolefins, polyacrylates, polymethacrylates, and copolymers thereof.
Also preferably, the supported phosphine compound is of Formula 1A: 
wherein Z is a divalent or trivalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NQxe2x80x94, where Q is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen; and L is a divalent linking group covalently attached to Z and to SS, selected from the group consisting of optionally-substituted chains of from 1 to 12 linear, branched, and cyclic carbon atoms. Most preferably, SS is polystyrene; L is xe2x80x94CH2xe2x80x94; Z is xe2x80x94(NQ)xe2x80x94; Q is selected from the group consisting of n-propyl, and t-butyl; R1 is selected from the group consisting of bromo, chloro, phenyl, methyl, i-propyl, mesityl, cyclohexyl, 3-methoxyphenyl, and 2-thienyl, xe2x80x94CH2CH(C2H5)CH2O(CH2)3CH3, and xe2x80x94CH2CH(C2H5)CH2OCH2C6H5; and R2 is selected from the group consisting 2-furanyl, 2-(5-methylfuranyl), 2-thienyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-N,N-dimethyl-5-toluidinyl, 4-pyrrolidino-3-pyridinyl, 2,5-dimethyl-1-N(4xe2x80x2-methylphenyl)pyrrolidinyl, 2,5-dimethyl-1-N-phenylpyrrolidinyl, and 2,5-dimethoxylphenyl.
This invention is directed to compositions and processes to prepare polymer-supported phosphine and phosphine oxide compounds and the corresponding free compounds after their cleavage from the polymer support.
More specifically, the invention is directed towards a process to prepare a supported phosphine compound of Formula 1: 
wherein SS is a solid support; R1 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R2 is selected from the group consisting of halogen, cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic. The process comprises the steps of: a) contacting a phosphine of the formula XPR1R2, wherein X is a halogen, with the solid support, resulting in the P in the phosphine attached indirectly or directly to the solid support via a covalent bonds, and b) optionally replacing one or more of R1 or R2 with any other R1 or R2.
Preferably, SS is selected from the group consisting of polyolefins, polyacrylates, polymethacrylates, and copolymers thereof.
Also preferably, the supported phosphine compound is of Formula 1A: 
wherein Z is a divalent or trivalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NQxe2x80x94, where Q is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen; and L is a divalent linking group covalently attached to Z and to SS, selected from the group consisting of optionally-substituted chains of from 1 to 12 linear, branched, and cyclic carbon atoms. Most preferably, SS is polystyrene; L is xe2x80x94CH2xe2x80x94; Z is xe2x80x94(NQ)xe2x80x94; Q is selected from the group consisting of n-propyl, and t-butyl; R1 is selected from the group consisting of bromo, chloro, phenyl, methyl, i-propyl, mesityl, cyclohexyl, 3-methoxyphenyl, and 2-thienyl, xe2x80x94CH2CH(C2H5)CH2O(CH2)3CH3, and xe2x80x94CH2CH(C2H5)CH2OCH2C6H5; and R2 is selected from the group consisting 2-furanyl, 2-(5-methylfuranyl), 2-thienyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-N,N-dimethyl-5-toluidinyl, 4-pyrrolidino-3-pyridinyl, 2,5-dimethyl-1-N(4xe2x80x2-methylphenyl)pyrrolidinyl, p-[(2,5-dimethyl)-1-pyrrolidinyl]phenyl, and 2,5-dimethoxylphenyl.
The invention is also directed towards supported phosphine compounds of Formula 1: 
wherein SS is a solid support; R1 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R2 is selected from the group consisting of cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic.
Preferably, SS is selected from the group consisting of polyolefins, polyacrylates, polymethacrylates, and copolymers thereof.
Also preferably, the supported phosphine compound is of Formula 1A: 
wherein Z is a divalent or trivalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NQxe2x80x94, where Q is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen; and L is a divalent linking group covalently attached to Z and to SS, selected from the group consisting of optionally-substituted chains of from 1 to 12 linear, branched, and cyclic carbon atoms. Most preferably, SS is polystyrene; L is xe2x80x94CH2xe2x80x94; Z is xe2x80x94(NQ)xe2x80x94; Q is selected from the group consisting of n-propyl, and t-butyl; R1 is selected from the group consisting of bromo, chloro, phenyl, methyl, i-propyl, mesityl, cyclohexyl, 3-methoxyphenyl, and 2-thienyl, xe2x80x94CH2CH(C2H5)CH2O(CH2)3CH3, and xe2x80x94CH2CH(C2H5)CH2OCH2C6H5; and R2 is selected from the group consisting 2-furanyl, 2-(5-methylfuranyl), 2-thienyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-N,N-dimethyl-5-toluidinyl, 4-pyrrolidino-3-pyridinyl, 2,5-dimethyl-1-N(4xe2x80x2-methylphenyl)pyrrolidinyl, 2,5-dimethyl-1-N-phenylpyrrolidinyl, and 2,5-dimethoxylphenyl.
By hydrocarbyl is meant a straight chain, branched or cyclic arrangement of carbon atoms connected by single, double, or triple carbon to carbon bonds and/or by ether linkages, and substituted accordingly with hydrogen atoms. Such hydrocarbyl groups may be aliphatic and/or aromatic. Examples of hydrocarbyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, benzyl, phenyl, o-tolyl, m-tolyl, p-tolyl, xylyl, vinyl, allyl, butenyl, cyclohexenyl, cyclooctenyl, cyclooctadienyl, and butynyl. Examples of substituted hydrocarbyl groups include methoxy, phenoxy, toluyl, chlorobenzyl, fluoroethyl, p-CH3xe2x80x94Sxe2x80x94C6H5, 2-methoxy-propyl, and (CH3)3SiCH2.
Virtually any solid material may be used as a support in the context of this invention as long as it meets the following criteria:
The material is insoluble in organic, aqueous, or inorganic solvents. Organic polymer supports are acceptable in this regard but they generally need to be crosslinked. Inorganic support, such as metal oxides (SiO2, Al2O3, TiO2, ZrO2, etc.), clays, and zeolites, and modified carbons are generally insoluble in these solvents and also may be used as supports.
The support contains reactive sites, which can be used for the covalent attachment of the phosphorus.
The reactive sites are isolated to prevent additional crosslinking during further chemical transformations.
The reactive sites are exposed to the reaction medium. With a polymer resin support this is achieved through the use of a resin which swells in a reaction solvent or is sufficiently porous to allow transport of the reaction medium through the polymer matrix.
The term xe2x80x9csolid supportxe2x80x9d refers to a material having a rigid or semi-rigid surface that contains or can be derivatized to contain functionality, which covalently links a compound to the surface thereof. Other modifications may be made in order to achieve desired physical properties. Such materials are well known in the art and include, by way of example, polystyrene supports, polyacrylamide supports, polyethyleneglycol supports, metal oxides such as silica, and the like. Such supports will preferably take the form of small beads, pellets, disks, films, or other conventional forms, although other forms may be used.
A preferred solid support is an organic or inorganic polymer, to which the phosphorus can be covalently attached through a side chain or pendant group of the polymeric backbone. The polymer may be crosslinked or modified. Suitable preferred polymers useful in the preparation of a supported phosphine compound or a combinatorial library of supported phosphine compounds include polyolefins, polyacrylates, polymethacrylates, and copolymers thereof that meet the general criteria described above. A more preferred polymeric support is polystyrene wherein the phosphorus is attached to a pendant phenyl group on the polystyrene backbone. Most preferred is polystyrene, crosslinked with divinylbenzene. Specifically, polystyrenes commonly used for solid phase synthesis have been used. These particular resins are crosslinked with from 1 to 10 wt % divinylbenzene. The styrene moieties are substituted in the para or meta positions. Only a portion of the styrene moieties are substituted, typically resulting in functional group loadings of approximately 0.2 to 2.0 mmole per gram of resin, although this value may be higher or lower.
Any reaction in which the phosphorus is covalently attached to the solid support may be used to prepare the compounds represented by Formula 1 and 1A, such as those described in Encyclopedia of Inorganic Chemistry, John Wiley and Sons, Vol. 6, pg. 3149-3213, herein incorporated by reference.
One embodiment of attaching the P to the solid support is via the reaction of the halogen or hydrogen bonded to the phosphorus in the phosphine with a nucleophilic group that is covalently attached to a solid support. The term nucleophilic group is a term well recognized in the art and refers to chemical moieties having a reactive pair of electrons. This scheme can easily be adapted for combinatorial synthesis.
Any of the substituents in the above compounds may be replaced by other functional groups using any procedure known in the art. One or all of the substituents can be reacted in a single reaction, depending on the choice of reactants and reaction conditions. These reactions can easily be adapted for combinatorial processes. These procedures and other procedures to prepare the compounds represented by Formula 1 and 1A are detailed in U.S. patent application Ser. No. 09/415,347, filed Oct. 8, 1999, herein fully incorporated by reference.
Any of the substituents in the above compounds may be replaced by other functional groups using any procedure known in the art. One or all of the substituents can be reacted in a single reaction, depending on the choice of reactants and reaction conditions.
The processes of the instant invention can easily be adapted for combinatorial processes and to create combinatorial libraries of the compounds of the instant invention. Additionally, the process of the instant invention can be used to prepare chiral phosphine compounds, without any loss of chirality present in the starting materials.
As used herein, a combinatorial library is an intentionally created collection of a plurality of differing molecules which can be prepared by selected synthetic means and screened for a desired activity or characteristic in a variety of formats (e.g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips, or other solid supports). The libraries are generally prepared such that the compounds are in approximately equimolar quantities, and are prepared by combinatorial synthesis. Combinatorial synthesis refers to the parallel synthesis of diverse compounds by sequential additions of multiple choices of reagents which leads to the generation of large chemical libraries containing related molecules having molecular diversity. Screening methods for libraries vary greatly and are dependent upon a desired activity, the size of library, and the class of compounds in the library.
The libraries of the instant invention can be of any type. These types include but are not limited to arrays and mixtures. Arrays are libraries in which the individual compounds are simultaneously synthesized in spatially segregated locations, typically identified by their location on a grid. Mixture libraries contain a mixture of compounds that are simultaneously synthesized and assayed. Identification of the most active compound is then performed by any of several techniques well known in the combinatorial art, such as deconvolution (Proc. Natl. Acad. Sci. USA, 91, pg. 10779 (1994)).
A preferred solid support for the combinatorial libraries of the instant invention is an organic or inorganic polymer as described above, to which the phosphorus can be covalently attached through a side chain or pendant group of the polymeric backbone.
The invention is also directed to a process to prepare a phosphine compound selected from the group consisting of Formula 2 and 3: 
wherein R4 is a halogen; R5 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R6 is selected from the group consisting of cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic; comprising the steps of: contacting a supported phosphine compound of the Formula 1: 
wherein SS is a solid support; R1 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; and R2 is selected from the group consisting of cyclic hydrocarbyl, substituted cyclic hydrocarbyl, heterocyclic and substituted heterocyclic with an compound of the Formula ER9, wherein E is an electrophilic group and R9 is selected from the group consisting of halogen, hydrocarbyl, substituted hydrocarbyl, heterocyclic and substituted heterocyclic; thereby forming the corresponding compound of Formula 1 and 2; and optionally replacing one or more of R4, R5, and R6 with any R4, R5, and R6.
Preferably the supported phosphine compound is of Formula 1A: 
wherein Z is a divalent or trivalent attaching group covalently attached to at least one phosphorus in the phosphine, selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NQxe2x80x94, where Q is selected from the group consisting of an optionally-substituted hydrocarbyl and halogen; and L is a divalent linking group covalently attached to Z and to SS, selected from the group consisting of optionally-substituted chains of from 1 to 12 linear, branched, and cyclic carbon atoms
Also preferably ER9 is selected from the group consisting of PCl3 and water. More preferably, L is xe2x80x94CH2xe2x80x94; Z is xe2x80x94(NQ)xe2x80x94; Q is selected from the group consisting of n-propyl, and t-butyl; R4 is chloro; R5 is selected from the group consisting of bromo, chloro, methyl, i-propyl, phenyl, xe2x80x94CH2CH(C2H5)CH2O(CH2)3CH3, and xe2x80x94CH2CH(C2H5)CH2OCH2C6H5; and R6 is selected from the group consisting of phenyl, 2-N,N-dimethyl-5-toluidinyl, 2-[(2,5-dimethyl)-1-pyrrolidinyl]-4-methylphenyl, 2,4-dimethoxyphenyl, and 2,5-dimethoxylphenyl.
In the above process, E is any electrophilic group that will cleave the covalent bond attaching the phosphorus to the solid support. The term electrophilic group is a term well recognized in the art and refers to chemical moieties, which can accept a pair of electrons from a nucleophilic group as defined above. Suitable electrophilic groups include trimethylsilyl, PCl2, halogens, and protons donated from compounds such as acids, water, alcohols, or amines.
In the instance where ER9 is water, the resulting POH group would rearrange to yield to form the compounds of Formula 3. These compounds can also be formed from any other of Formula 2 via the replacement of one or more of R4, R5, and R6 with an xe2x80x94OH group using any method known in the art. An equivalent rearrangement occurs when a PSH group is present.
Any of the substituents in the above compounds may be replaced by other functional groups. One or all of the substituents can be reacted in a single reaction, depending on the choice of reactants and reaction conditions. These reactions can easily be adapted for combinatorial processes. These procedures and other procedures to prepare the compounds represented by Formula 1 and 1A are detailed in U.S. patent application Ser. No. 09/415,347, filed Oct. 8, 1999, herein fully incorporated by reference.
The processes of the instant invention can easily be adapted for combinatorial processes and to create combinatorial libraries of the compounds of the instant invention. Additionally, the process of the instant invention can be used to prepare chiral phosphine compounds, without any loss of chirality present in the starting materials. To create a library, one or more supported phosphines are reacted with one or more compounds of the Formula ER9, generating a plurality of phosphine compounds.
The processes of the instant invention are preferably performed under dry, inert atmosphere with dry, deoxygenated solvents. Any solvent is suitable provided that it is inert to all reagents and products. Optimum temperatures are about xe2x88x9280 to about 200xc2x0 C., preferably about xe2x88x9280 to about 150xc2x0 C.
The phosphorus compounds and libraries described herein, both supported and unsupported, can be utilized as ligands for catalytic compounds. The compounds can be complexed with one or more transition metals to form a coordination compound.
xe2x80x9cCoordination compoundxe2x80x9d refers to a compound formed by the union of a metal ion (usually a transition metal) with a non-metallic ion or molecule called a ligand or complexing agent.
The transition metals are hereby defined as metals of atomic number 21 through 83. Preferably, the transition metal is from Periodic Group VIII, hereby defined as Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, and Pt. Preferred is Pd. The complex can be made by any synthetic method known in the art, either through direct reaction or via the use of a transition metal precursor. Many of these techniques are described in Hartley, xe2x80x9cChem. Met.-Carbon Bondxe2x80x9d, Hartley, F. R (Ed), 1987, vol. 4, pp. 1163-1225.
One reaction in which the compounds of the instant invention can be utilized as catalysts is in the cross-coupling of aryl halides with thiols. This type of reaction is described in Zheng, et al., J. Org. Chem., 63, p9606-9607, 1998.
The following non-limiting Examples are meant to illustrate the invention but are not intended to limit it in any way.
All manipulations of air-sensitive materials were carried out with rigorous exclusion of oxygen and moisture in Schlenk-type glassware on a dual manifold Schlenk line, interfaced to a high-vacuum (10xe2x88x924-10xe2x88x925 Torr) line, or in a nitrogen-filled Vacuum Atmospheres glovebox with a high-capacity recirculator (1-2 ppm of O2). Before use, all solvents were distilled under dry nitrogen over appropriate drying agents (sodium benzophenone ketyl, metal hydrides except for chlorinated solvents). THF-D8C6D6 and CDCl3 were purchased from Cambridge Isotopes (Andover, Mass.). All organic and inorganic starting materials were purchased from Aldrich Chemical Co. (Milwaukee Wis.), Farchan Laboratories Inc. (Gainesville, Fla.), Strem Chemicals (Newburyport, Mass.), Calbiochem-NovaBiochem Corp. (San Diego, Calif.), Rieke Metals, Inc. (Lincoln, Nebr.), or Lancaster Synthesis Inc. (Windham, N.H.), and when appropriate were distilled prior to use.
NMR spectra were recorded on either a Nicolet NMC-300 wide-bore (FT, 300 MHz, 1H; 75 MHz, 13C, 121 MHz 31P), or GE QM-300 narrow-bore (FT, 300 MHz, 1H) instrument. Chemical shifts (xcex4) for 1H, 13C are referenced to internal solvent resonances and reported relative to SiMe4. 31P NMR shifts are reported relative to external phosphoric acid. Analytical gas chromatography was performed on a Varian Model 3700 gas chromatograph with FID detectors and a Hewlett-Packard 3390A digital recorder/integrator using a 0.125 in. i.d. column with 3.8% w/w SE-30 liquid phase on Chromosorb W support. GC/MS studies were conducted on a VG 70-250 SE instrument with 70 eV electron impact ionization.